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Obstetric haematology training: Optimising care through cultivated expertise
Get PDFBackgroundObstetric Haematology, a subspecialty at the interface of Obstetric Medicine, Haematology and Maternal-Fetal Medicine, addresses the complex interplay between pregnancy and haematological disorders. Advances in survival and reproductive technologies have increased the number of individuals with complex haematological conditions achieving pregnancy, underscoring the need for specialised expertise. Exposure to expertise may vary significantly by training program and formal training in Obstetric Haematology remains limited.Methods and resultsA narrative review was conducted and an approach for Obstetric Hematology training is proposed consisting of a structured curriculum incorporating reproduction planning, contraception, medication safety, haematological adaptations of pregnancy, and psychosocial support.ConclusionThe development of an Obstetric Haematology curriculum can standardize education and enhance multidisciplinary collaboration with a target of improving outcomes for pregnant individuals with haematological disorders. Next steps include comprehensive needs assessment across specialties, definition of core competencies through consensus approaches, and incorporation of patient perspectives in curriculum design
Risk prediction in patients with heart failure with preserved ejection fraction: the LIFE-Preserved model
Get PDFBackground and aims: Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes a heterogeneous disease with varying prognosis. Given the rising incidence of HFpEF, accurate risk prediction for these patients is needed to identify high-risk individuals, who may benefit the most from preventive treatments. The LIFE-Preserved model was developed and validated for the prediction of individual short-term and lifetime risk for HF hospitalization or cardiovascular (CV) death in patients with HFpEF. Methods: LIFE-Preserved was derived in 20,332 patients aged 40-90 years with a left ventricular ejection fraction ≥50% from the Swedish HF Registry (SwedeHF). Cause- and sex-specific Cox models were derived to predict the risk of HF hospitalization or CV death using 14 routinely available predictors. Use of age as the timescale allowed for predictions beyond the maximum follow-up duration in the derivation data, adjusted for competing risks. External validation was performed in two trials (EMPEROR-Preserved, TOPCAT-Americas) and three registries (NHS England Secure Data Environment, Veterans Affairs, HF-Particles). Model performance was assessed by discrimination and calibration. Results: During a median follow-up of 1.8 years (interquartile range 0.6–4.2, maximum 19 years), 9341 first HF hospitalizations or CV deaths (46%) were observed in SwedeHF. External validation included data from 28 062 patients with HFpEF (9930 [35%] first HF hospitalizations or CV deaths). Pooled C-statistics were 0.714 (95% confidence interval [CI] 0.652–0.775) in trials and 0.658 (95% CI 0.599–0.717) in registries, with adequate calibration in all external validation sources. Performance was similar in men and women. An interactive calculator of the LIFE-Preserved model has been made available here. Conclusions: The LIFE-Preserved model enables prediction of short-term and lifetime risk of HF hospitalization or CV death in patients with HFpEF. The model could serve as a tool to identify high-risk HFpEF patients, guiding clinical management and shared decision-making
Large-scale distribution of cestode infections in wild gentoo penguins and their impact on the host microbiome
Get PDFIntestinal helminths often cause chronic infections, which can impact health and productivity, particularly when combined with other stressors including the environmental challenges faced by polar species. Here we employed a faecal DNA amplicon-sequencing-based approach to study on the epidemiology of tapeworms (Cestoda) in gentoo penguins sampled from colonies within the Scotia Arc. Overall, 325 faecal samples were collected from gentoo penguins at 25 locations and screened for cestode sequences within a pan-eukaryote 18S DNA profile. Four different core groups of sequences were identified as frequently occurring in the dataset, which likely represent different species or groups of cestodes. The proportion of cestode DNA reads was highly variable, displaying an over-dispersed distribution. The proportion of cestode DNA correlated with differences in microbiome composition, suggesting that these infections may influence gut microbiota or vice versa, with broader consequences for penguin health and resilience. This study highlights the need for a comprehensive understanding of both direct and indirect effects of helminths on individual and population health
Systematics mitigation for catalogue-based angular power spectra
Get PDFRecent work has developed a formalism for computing angular power spectra directly from catalogues containing field values at discrete positions on the sky, thereby circumventing the need to create pixelized maps of the fields, as well as avoiding aliasing and finite-resolution effects. We adapt this formalism to incorporate template deprojection for mitigating systematic biases in the measured angular power spectra. We also introduce an alternative method of mitigating the ‘deprojection bias’ – the loss of modes induced by deprojection – employing simple simulations to compute a transfer function. We find that this approach performs at least as well as existing methods, and is relatively insensitive to how well one can guess the true power spectrum of the observed field, except at the largest scales (). Additionally, we develop exact expressions for the bias introduced by deprojection in the shot-noise component, which further improves the accuracy of this approach. We test our formalism on simulated data sets, demonstrating its applicability both to discretely sampled fields, and to the special case of galaxy clustering, with the survey selection function defined in terms of a random catalogue or as a continuous sky map. After removing the bias in the shot noise and correcting for the remaining mode loss using a transfer function, our formalism produces unbiased measurements of the angular power spectrum in all scenarios tested here. Finally, we apply our formalism to real data and show it produces results consistent with the standard map-based pseudo- formalism. We implement our method in the public code NaMaster
The two edges of the Gordian Knot: religion, nationalism, and citizenship in Israel
No full textThis chapter explores the intricate relationship between religion and nationalism in Israel, focusing on the institutional, legal, and societal roles of religion in the formation of Israeli society. Through historical analysis from the British Mandate era to contemporary legislation, it demonstrates how religion serves as both an external and internal gatekeeper for Jewish Israeli collective identity while marginalizing Palestinians. The chapter identifies five pivotal moments: the establishment of the Chief Rabbinate (1921), the Status Quo Letter (1947), the creation of the Ministry of Religious Affairs and Interior, early legislation including the Law of Return and Absentees’ Property Law (1950), and recent laws such as the Nakba Law (2011) and Basic Law: Israel as the Nation-State of the Jewish People (2018). The chapter reveals that Judaism operates as a hegemonic religion, serving national purposes for Jewish Israelis, while Islam is reframed as a tool for depoliticizing and denationalizing Israeli Palestinian citizens. This dual epistemological formation creates a Gordian knot between religion, nationalism, and citizenship, establishing Israel as a unique case where national and colonial framings of religion merge under the same institutional framework, ultimately maintaining Jewish supremacy and Palestinian exclusion from full civic participation
Variation in antiviral immunity and inflammation pathways precedes HIV-1 infection in a high-risk African cohort
Get PDFBackgroundSusceptibility to human immunodeficiency virus type 1 (HIV-1) infection varies between individuals, but the biological determinants of acquisition risk remain poorly defined.MethodsWe conducted a case-control study nested within a high-risk cohort in Kenya. We compared the plasma extracellular RNA collected before HIV-1 acquisition with matched uninfected controls to identify immunological processes linked to infection risk.ResultsIndividuals who later acquired HIV-1 exhibited upregulation of immune processes that facilitate viral infection, including T cell suppression, type II interferon and Th2 immune responses. In contrast, processes associated with antiviral defence and tissue repair, such as neutrophil and natural killer cell responses, type I interferon responses, wound healing, and angiogenesis, were downregulated.ConclusionThese findings highlight dampened antiviral immunity prior to exposure as a correlate of increased risk for subsequent HIV-1 acquisition.Trial numbersNot applicable.FundingThis work was supported by a Wellcome Trust Award (209289/Z/17/Z) and the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) through the DELTAS Africa programme [Del-22-007], supported by the Science for Africa Foundation, Wellcome Trust, the UK Foreign, Commonwealth & Development Office, and the European Union. Additional support was provided by the Bill & Melinda Gates Foundation, Gilead Sciences Inc., Aidsfonds, and the Ragon Institute of Mass General, MIT, and Harvard. The cohort study was supported by PEPFAR through USAID. The views expressed are those of the authors
Tumour-intrinsic features shape T cell differentiation through precursor to symptomatic multiple myeloma
Get PDFMultiple myeloma (MM) is associated with skewed T cell activation and function which is present in asymptomatic myeloma precursor conditions, but underlying mechanisms of progression remain undefined. Here, we assemble a large single-cell RNA sequencing dataset of the bone marrow and blood from patients with MM, precursor conditions, and non-cancer controls. We demonstrate that, unlike solid cancers, MM is not characterized by T cell exhaustion, but by antigen-driven terminal memory differentiation. This is influenced by tumour-intrinsic features including tumour burden and expression of antigen-presentation genes. Expanded TCR clones accumulating in MM are not enriched with viral specificities but accumulate in effector states in highly-infiltrated marrows. Additionally, we identify a role for T cell dynamics in patients treated with autologous stem cell transplantation and demonstrate T cell features predict progression from precursor to symptomatic MM. Together, these results suggest that anti-tumour immunity drives a distinctive form of cancer-associated T cell differentiation in MM
Identifying pathogenic mechanisms in SYK gain-of-function inflammatory disease
No full textSpleen tyrosine kinase (SYK) is a signalling intermediate that is highly expressed in innate immune cells and B lymphocytes, where it has critical roles downstream of multiple immunoreceptors. Gain-of-function (GOF) variants in SYK cause severe immune dysregulation; leading to monogenic inflammatory bowel disease, multi-system inflammation, and humoral immunodeficiency. Studying monogenic immune disorders provides valuable insights into mechanisms that drive inflammation. These insights can inform precision therapies for affected individuals and enhance understanding of pathways relevant to polygenic diseases. This thesis investigates the pathogenic mechanisms underlying SYK GOF immune dysregulation, primarily using a SYK-S544Y GOF mouse model.SYK GOF causes a complex B cell immunodeficiency. In the bone marrow, a partial block in pre-B cell development limits transitional B cell output. In the spleen, transitional B cells preferentially differentiate into marginal zone B cells, further reducing the pool of naïve follicular B cells. Those that do develop exhibit increased activation and defective class-switch recombination. These abnormalities are associated with impaired humoral responses to model antigens and defective immunity to intestinal Citrobacter rodentium infection. Single-cell analysis of intestinal B cells from a SYK GOF patient revealed conserved features between the human and murine phenotypes.In addition to immunodeficiency, SYK GOF mice develop intestinal inflammation following colonisation with Helicobacter hepaticus, a gram-negative pathobiont normally tolerated by the mucosal immune system. The mice also develop a spontaneous peripheral and axial spondyloarthropathy which shares clinical, radiological, and histological features with human axial spondyloarthritis. Despite the pronounced B cell abnormalities, both Helicobacter-induced colitis and spontaneous arthritis developed in Rag-deficient SYK GOF mice, indicating that innate immune cells play a primary role in disease pathogenesis. A shared transcriptional signature was identified in colitis and arthritis, characterised by increased expression of genes associated with chronic inflammatory macrophages, pattern recognition receptor signalling, and pro-inflammatory cytokines. These findings were supported by in vitro studies, in which SYK GOF bone marrow-derived macrophages showed enhanced inflammatory responses to TLR2/6, TLR4, TLR9, and NOD2 ligands.This thesis identifies aberrant PRR signalling in macrophages as a central pathogenic mechanism in SYK GOF associated inflammatory disease. These findings deepen our understanding of SYK as a key regulator of innate immune responses, suggest broader relevance of SYK signalling pathways in the pathogenesis of IBD and spondyloarthropathy, and support the potential of SYK as a therapeutic target in inflammatory diseases
Beyond regional economic resilience: unravelling cluster resilience in the polycrisis era
Get PDFThis study distinguishes cluster resilience from regional economic resilience, which often overlooks heterogeneous mechanisms within clusters. Drawing on a two-decade comparison of two Chinese furniture clusters, it shows how adaptive capacities are shaped by dual embeddedness in territorial contexts and wider industrial networks. One cluster, located in an underdeveloped region with a simple industrial network, relies on direct government intervention to remain resilient. The other, embedded in a diversified and advanced economy, draws resilience from market dynamics and cross-industry synergies. The study demonstrates how institutional and industrial network contexts interact to produce distinct adaptive pathways during periods of polycrisis